CN115626946A - 一种桦木醇-卡洛芬衍生物及其自组装纳米颗粒和在制备抗肺癌药物中的用途 - Google Patents
一种桦木醇-卡洛芬衍生物及其自组装纳米颗粒和在制备抗肺癌药物中的用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于天然药物领域,特别涉及一种桦木醇-卡洛芬衍生物及其自组装纳米颗粒和在制备抗肺癌药物中的用途。
背景技术
肺癌是世界上最常见的恶性肿瘤之一,已成为我国城市人口恶性肿瘤死亡原因的第1位;其中非小细胞型肺癌(NSCLC)约占肺癌的80%,包括鳞癌、腺癌、大细胞癌;约75%患者处于中晚期发现,目前化疗是主要治疗手段,5年生存率很低。化疗对患者的正常细胞存在巨大破坏,肺癌易产生药物耐药性,且局部复发率和全身转移率高,疾病预后差。因此,有靶向性地抑制肺癌细胞生长的方法,仍然是NSCLC治疗的希望所在。
桦木醇(Betulin,BE;C30H50O2;MW,442.72)是一种属难溶性的五环三萜类化合物,广泛存在于如中国油茶、白桦树、在酸枣仁、白桦树、滇刺枣等多种植物中,尤其是申请人课题组新发现BE在油茶饼中高含量富集存在,具有油茶副产物二次深入开发价值。研究发现,BE的毒性非常小,对肿瘤、艾滋病病毒、炎症免疫、细菌/寄生虫等方面具有广泛活性(中草药,2014;45(14):2118-24.),是具有前途的药物前体之一。非常有趣地是,BE类化合物可选择性地杀伤癌细胞,而对正常细胞无明显毒性,两者之间选择性差10倍。鉴于其非常特别的选择性差异,BE母核显示出其良好的抗肿瘤药物开发前景;但由于溶解性差导致其生物利用度低和靶细胞的内吞不足,限制其作为治疗药物系统的应用。因此,借助纳米技术和化学修饰改善这类化合物的成药性十分必要。
随着对BE类化合物母核构效关系研究,发现修饰主要集中在三个位置:C-3位、C-20位和C-28位;如CN104387440A,CN200610119542,CN104271550B,CN106589046A,CN107892709A,CN108026139A,CN200610067268等专利公开了包括桦木醇、桦木酸等五环三萜类化合物的修饰药物研究。其中,化合物DSB(YK-FH312),RPR103611,PA457(Bevirimat)和NVX-207已经处于抗HIV或抗癌的临床试验阶段;但由于其水溶性太差,仍然存在生物利用度低和体内药代/摇动等方面的缺点。
卡洛芬(Carprofen,CP;C15H12ClNO2;MW:273.71)是一种强效消炎、镇痛和解热作用的关节炎/风湿用药物,具有口服吸收快、达峰时间短、血浆蛋白结合率高达99%、副作用小的特点。分子机理为抑制前列腺素的合成,阻断炎症介质而起作用。
近年来,抗炎已是抗肿瘤协同治疗的一种手段之一。基于肿瘤细胞内特异高表达的碳酸酯酶和对碳酸酯键特异响应的设计原理(Int J Cancer.2013;133(2):408-15.;BrJ Pharmacol.2013;168(8):1989-99.;J Clin Invest.2021;131(11):e137845.;),本发明从靶向抗癌前体BE出发,将BE上的OH偶联2分子CP成前药BP,促进CP被肿瘤细胞内吞,达到抗炎增效抗癌和强脂溶性组装成纳米颗粒,利用肿瘤细胞的增强渗透和滞留(EPR)效应,实现其纳米颗粒被用于肺癌靶向治疗。
发明内容
为了克服现有技术中存在的缺点和不足,本发明的首要目的在于提供一种桦木醇-卡洛芬衍生物(BP)。
本发明的再一目的在于提供一种上述桦木醇-卡洛芬衍生物的制备方法。
本发明的另一目的在于提供一种上述桦木醇-卡洛芬衍生物的自组装纳米颗粒。
本发明的又一目的在于提供一种上述桦木醇-卡洛芬衍生物或其自组装纳米颗粒在制备抗肺癌药物中的用途。
本发明的目的通过以下技术方案实现:
一种桦木醇-卡洛芬衍生物,所述桦木醇-卡洛芬衍生物具有如下结构式:
上述的桦木醇-卡洛芬衍生物的制备方法,包括以下操作步骤:在无水二氯甲烷溶剂中用草酰氯使卡洛芬(CP)的羧基转化,得到酰氯卡洛芬;在无水二氯甲烷和室温条件下,三乙胺作缚酸剂,将酰氯卡洛芬与桦木醇(BE)反应,得到目标产物桦木醇-卡洛芬衍生物(BP)。
上述的制备方法,具体包括以下操作步骤:
(1)室温下,取卡洛芬加入无水二氯甲烷溶剂中,磁力搅拌均匀后,滴加DMF作为催化剂,再加入草酰氯,用带干燥器的塞子封闭进行反应6~12小时;减压浓缩,除去溶剂以及多余的草酰氯,得到的浓缩液,即得到中间产物酰氯卡洛芬;
(2)立即将中间产物酰氯卡洛芬用二氯甲烷溶解搅拌均匀,加入无水三乙胺作为去酸剂,然后加入桦木醇,TLC监测反应进程,反应5~12小时完成后,用乙酸乙酯稀释,然后用稀盐酸和饱和氯化钠水溶液分别洗涤三次,经减压浓缩,干燥后,得到目标化合物桦木醇-卡洛芬衍生物。
步骤(1)所述室温是指20-30℃;所述卡洛芬的用量为0.5~1.0mmol,所述无水二氯甲烷溶剂的用量为20mL,所述DMF的用量为1-4滴,所述草酰氯的用量为10mmol;
步骤(2)所述二氯甲烷的用量为20mL,所述无水三乙胺的用量为2-4mL,所述桦木醇的用量为0.6mmol;所述乙酸乙酯的用量为100~200mL;所述洗涤是每次使用100mL稀盐酸或饱和氯化钠水溶液。
一种桦木醇-卡洛芬衍生物的自组装纳米颗粒,该自组装纳米颗粒是由权上述的桦木醇-卡洛芬衍生物自组装而成。
上述的桦木醇-卡洛芬衍生物或其药学上可接受的盐在制备抗肺癌药物中的用途。
一种具有抗肺癌活性的药物组合物,其中含有治疗有效量的上述的桦木醇-卡洛芬衍生物或其药学上可接受的盐。
上述的桦木醇-卡洛芬衍生物的自组装纳米颗粒在制备抗肺癌药物中的用途。
本发明在具体实施方式中对桦木醇-卡洛芬衍生物的合成、体外和体内药理活性会做进一步阐述。
与现有技术相比,本发明具有如下优点及有益效果:
(1)基于碳酸酯酶特异高表达和降解碳酸酯键,本发明将桦木醇和卡洛芬通过碳酸酯偶联成BP,结合了抗炎药物和抗肿瘤药物的优势基团,二者协同发挥抗癌/抗炎效应,该技术尚未见相关报道。
(2)本发明利用BP组合桦木醇-卡洛芬衍生物的疏水/亲水基团,使其具有自组装纳米药物特性;其对肺癌(A549、H1299、H460和LTEP-78细胞系)的增殖具有显著抑制作用,而对正常细胞系无生长抑制作用;皮下移植A549荷瘤裸鼠的抑制效应表明,BP显著抑制A549细胞的生长,且未见毒性。
附图说明
图1为BP的化学合成制备流程;
图2为BP自组装纳米颗粒的透射电镜图;
图3为BP在肺癌细胞裂解液和碳酸酯酶孵化的释放情况(**,p<0.01);
图4为BE、CP及BP抑制A549肿瘤体积生长的曲线(**,p<0.01);
图5为BE、CP及BP抑制A549荷瘤组织体重的比较(**,p<0.01);
图6为BE、CP及BP对A549荷瘤小鼠的体重影响曲线(*,p<0.05);
图7为BE、CP及BP对A549荷瘤小鼠的主要器官影响(ns,无统计差异)。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。
实施例1:BP的合成(合成制备流程如图1所示)
(1)室温下,取卡洛芬(CP)(1.0mmol),加入20mL的无水二氯甲烷溶剂中,磁力搅拌均匀后,加入3滴DMF为催化剂,再缓慢加入草酰氯(1.0mL,10mmol),用带干燥器的塞子封闭进行反应8小时;减压浓缩,除去溶剂以及多余的草酰氯,得到的浓缩液,即得到如下结构式的中间产物酰氯卡洛芬;
(2)立即将中间产物酰氯卡洛芬用20mL二氯甲烷溶解搅拌均匀,加入2mL无水三乙胺作为去酸剂,然后加入桦木醇(BE)(0.6mmol),TLC监测反应进程,反应5~12小时完成后,用200mL乙酸乙酯稀释,然后用稀盐酸和饱和氯化钠水溶液洗涤三次(每次洗涤采用100mL稀盐酸或饱和氯化钠水溶液进行洗涤),经减压浓缩,干燥后,得到白色目标化合物桦木醇-卡洛芬衍生物(BP)(产率~70%)。
目标产物BP的质谱和光谱数据如下:
ESI-MS(m/z):[M+H]+为955.0,[M+Na]+为978.1;1H-NMR:δ:11.78,2NH;8.13,2H;7.60~7.67,8H;7.11,2H;5.11,1H(CH=);4.93,1H(CH=);4.43,1H;4.09,1H;3.82,1H;3.71,2H;2.11,1H;1.78~1.81,4H;1.35~1.65,25H;0.85~1.01,19H。从而确定目标产物BP的分子式为C60H70Cl2N2O4,理论分子量应为954.1;具体结构如下所示:
实施例2:BP的自组装制备及粒径表征
室温下,将50mL去离子水于磁力搅拌器上搅拌均匀,将20mg实施例1合成所得的BP溶于DMSO溶剂中;然后,在磁力搅拌的条件下,用20μL的移液器吸取后进行缓慢滴加,然后用MW~1000的透析袋装载,在5000mL大烧杯中用去离子水透析24小时,即得尺寸均一的自组装纳米颗粒。用DLS测定仪检测其水合粒径约为200nm,PDI=0.28;其干燥后的粒径形态,通过高分辨透射电镜进行表征鉴定,约100nm左右(图2所示)。
实施例3:肺癌细胞裂解液和羧酸酯酶对实施例1所得BP的释放响应特性研究
首先,测定细胞内羧酸酯酶的方法,对肺癌细胞A549和H1299,正常肝脏细胞LO2和健康志愿者的外周血淋巴细胞(PBMC)中羧酸酯酶(CE)的活力进行测定,具体参考文献的方法进行实验(Wu X,Wang R,Qi S,Kwon N,Han J,Kim H,Li H,Yu F,Yoon J.RationalDesign of a Highly Selective Near-Infrared Two-Photon Fluorogenic Probe forImaging Orthotopic Hepatocellular Carcinoma Chemotherapy.Angew Chem Int EdEngl.2021;60(28):15418-15425.),比较CE在正常细胞和肺癌细胞中的含量区别(图3中的A所示),结果表明:CE在肺癌细胞中具有显著性高表达,可作为肺癌前药释放的响应酶。
然后,将20μM的BP加或不加20μM碳酸酯酶抑制剂(Is-p-nitrophenyl phosphate,BNPP),与购买的羧酸酯酶CE(2U/mL;Sigma)和不同细胞裂解液CE酶在生理盐水中进行37℃孵化不同时间点,分别对其释放的CP片段在235nm和210nm波长下分别对CP和BE进行HPLC检测;实验结果表明,BP前药设计具有显著的肺癌响应特性(图3中的B和C所示)。
实施例4:BP抗癌细胞增殖的研究
购于上海细胞库的肺癌细胞株A549、H1299、H460和LTEP-78;前列腺癌PC-3,肝癌细胞HepG2,胃癌细胞MGC-803,乳腺癌MCF-7和结直肠癌细胞HCT-116及健康志愿者来源的肝脏细胞系LO2,正常胚肾细胞HEK293T,采用10%的胎牛血清和DMEM或1640培养基进行培养增殖;通过淋巴细胞分离液获取健康志愿者外周血淋巴细胞(PBMC),用20%的胎牛血清和1640培养基进行培养和药物毒性评价;所述细胞均由本发明人课题组进行复苏、传代、培养及冻存等。
5%CO2,37℃培养箱中(相对湿度90%)培养环境;取对数生长期的细胞,分别接种2×104肺癌细胞/孔于96孔板上待生长6小时后,离心弃上清;然后按以下分组给药:肿瘤细胞设不加药组和BP加药组,每组设5个复孔,培养24或72小时,弃上清,加入100μL含0.5mg/mL的MTT(四氮唑盐)无血清培养液培养4小时,加入100μL二甲亚砜(DMSO),放置于酶标仪上进行60s自动振荡,再用570nm处检测OD值。PBMC按6×104/孔直接与药物进行孵化。结果按照以下抑制率公式计算每种情况下肿瘤细胞生长的抑制率,具体结果见表1。
抑制率(%)=(1-加药组OD值/对照组OD值)×100%
表1为BE、CP、BE+2CP(BE和CP按照摩尔比1:2混合)和BP给药作用不同细胞不同时间后的IC50。从表中,我们可以发现,BP用于肺癌细胞治疗的选择性更好。
表1作用不同癌细胞系和正常细胞抑制率
实施例5:BP抗肺癌A549皮下瘤的体内效应
将BALB/C裸鼠适应SPF动物房环境条件7天(6周龄,体重(17.8±g),雌性,由斯莱克实验动物技术有限公司提供),自由饮水饮食,室温(22±1)℃,湿度(40±10)%,光照周期12小时/12小时(白夜交替)。
取0.1mL的肺癌A549细胞,用消毒酒精棉球擦拭干净,1mL注射器抽取肿瘤细胞,将其接种于裸鼠左腋皮下,待裸鼠移植瘤长至体积100±mm3时,随机分组。腹腔注射给药,末次给药后停药2天处理;每2天称量裸鼠体重和测量移植瘤体积一次,每次测量移植瘤的长径(L)和与之垂直的短径(W),根据TV=L×W2/2计算肿瘤体积,绘制各组移植瘤的生长曲线。同时,记录化合物对荷瘤裸鼠体内肿瘤生长的影响,分析用药前后分别称取各组荷瘤裸鼠肿瘤组织的重量,比较各组主要器官的差异情况。
实验结果如图4-7所示,荷瘤裸鼠口服5%玉米油(溶媒组和溶解药物)和10mg/kg/天的BP及等摩尔的BE和CP化合物干预14天后,第15天麻醉处死小鼠,结果表明,只有BP明显抑制A549肿瘤生长(图4),肿瘤体积和重量的抑制率均大于50%(图5),对小鼠体重和主要器官重量的影响无显著性变化(图6和图7),与其他组比较,BP在体内对肺癌具有显著抑瘤效应,且尚未发现毒副作用。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (8)
2.根据权利要求1所述的桦木醇-卡洛芬衍生物的制备方法,其特征在于包括以下操作步骤:在无水二氯甲烷溶剂中用草酰氯使卡洛芬的羧基转化,得到酰氯卡洛芬;在无水二氯甲烷和室温条件下,三乙胺作缚酸剂,将酰氯卡洛芬与桦木醇反应,得到目标产物桦木醇-卡洛芬衍生物。
3.根据权利要求2所述的制备方法,其特征在于具体包括以下操作步骤:
(1)室温下,取卡洛芬加入无水二氯甲烷溶剂中,磁力搅拌均匀后,滴加DMF作为催化剂,再加入草酰氯,用带干燥器的塞子封闭进行反应6~12小时;减压浓缩,除去溶剂以及多余的草酰氯,得到的浓缩液,即得到中间产物酰氯卡洛芬;
(2)立即将中间产物酰氯卡洛芬用二氯甲烷溶解搅拌均匀,加入无水三乙胺作为去酸剂,然后加入桦木醇,TLC监测反应进程,反应5~12小时完成后,用乙酸乙酯稀释,然后用稀盐酸和饱和氯化钠水溶液分别洗涤三次,经减压浓缩,干燥后,得到目标化合物桦木醇-卡洛芬衍生物。
4.根据权利要求3的制备方法,其特征在于:步骤(1)所述室温是指20-30℃;所述卡洛芬的用量为0.5~1.0mmol,所述无水二氯甲烷溶剂的用量为20mL,所述DMF的用量为1-4滴,所述草酰氯的用量为10mmol;
步骤(2)所述二氯甲烷的用量为20mL,所述无水三乙胺的用量为2-4mL,所述桦木醇的用量为0.6mmol;所述乙酸乙酯的用量为100~200mL;所述洗涤是每次使用100mL稀盐酸或饱和氯化钠水溶液。
5.一种桦木醇-卡洛芬衍生物的自组装纳米颗粒,其特征在于:该自组装纳米颗粒是由权利要求1所述的桦木醇-卡洛芬衍生物自组装而成。
6.根据权利要求1所述的桦木醇-卡洛芬衍生物或其药学上可接受的盐在制备抗肺癌药物中的用途。
7.一种具有抗肺癌活性的药物组合物,其中含有治疗有效量的权利要求1所述的桦木醇-卡洛芬衍生物或其药学上可接受的盐。
8.根据权利要求5所述的桦木醇-卡洛芬衍生物的自组装纳米颗粒在制备抗肺癌药物中的用途。
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